WO1992005171A1 - Imidazoline derivatives - Google Patents
Imidazoline derivatives Download PDFInfo
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- WO1992005171A1 WO1992005171A1 PCT/GB1991/001542 GB9101542W WO9205171A1 WO 1992005171 A1 WO1992005171 A1 WO 1992005171A1 GB 9101542 W GB9101542 W GB 9101542W WO 9205171 A1 WO9205171 A1 WO 9205171A1
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- efaroxan
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- This invention relates to imidazoline derivatives, their salts, process for their preparation and pharmaceutical compositions thereof.
- R 1 is hydrogen or alkyl C 1-6 ;
- R 2 is hydrogen, methyl, chloro, bromo or fluoro;
- R 3 is hydrogen, methyl, hydroxy, methoxy, fluoro, chloro or bromo; and their non-toxic salts.
- the compounds of Formula A contain an asymmetric carbon atom and the invention emoraces both the racemic mixtures and the optically active enantiomers. All the compounds exemplified mere in the form of the racemates.
- the compounds of Formula A possessed ⁇ 2 -adrenoreceptor antagonist activity and by virtue of such activity had potential utility for the treatment of those conditions in patients in which activity at the ⁇ 2 -adrenoreceptors was implicated such as endogenous depression, cardiac failure, diabetes, obesity, migraine etc.
- R is hydrogen or methyl, in substantially pure form, and its non-toxic salts.
- (+) enantiomer of a compound of Formula 1 in substantially pure form we mean that the amount of the (+) enantiomer present does not exceed 5% and preferably does not exceed 2% .
- non-toxic salts are those with inorganic salts such as hydrochloric acid, sulphuric or phosphoric acid; or organic acids such as acetic, propionic, malonic, succinic, fumaric, tartaric or citric acid.
- a preferred salt is the hydrochloride.
- the invention also includes pharmaceutical compositions comprising the (-) enantiomer of a compound of Formula 1 in substantially pure form or a non-toxic salt thereof, together with a pharmaceutically acceptable diluent or carrier.
- potassium permeability (potassium channel opening) reduces insulin secretion whereas the converse is true with potassium channel blockade.
- a number of drugs affect potassium channel permeability and the antidiabetic sulphonylureas function as potassium channel blockers.
- the vasodilator diazoxide which can induce a diabetic state, increases botassium channel permeability and therefore reduces insulin secretion.
- the ⁇ 2 -adrenoreceptor agonist employed in these studies was p-aminoclonidine.
- the in vivo prejunctional ⁇ 2 -adrenoreceptor antagonist potencies were determined in the vas deferens of pithed rats using a previously described method (Welbourn et al, J Med Chem, 1986, 29, 2000). Antagonist potencies were determined as the dose ( ⁇ moles/Kg, iv) required to produce a 2-fold shift (DR2) of the dose-response curve to UK-14304 on the twitch response of the vas deferens.
- the radioligand binding affinities were determined from their ability to displace the saturable binding of [ 3 H] idazoxan from ⁇ 2 -adrenoreceptor sites prepared from rat cerebral cortical membranes (Welbourn et al, J Med Chem, 1986, 29, 2000).
- (+) but not (-) efaroxan This confirms that the ⁇ 2 - antagonist activity resides in the (+) enantiomer in pancreatic islets as well as in non-islet cells.
- Fig 2 shows that insulin secretion stimulated by 20mM glucose can also be inhibited by diazoxide, a known K + channel opening agent, and this effect is reversed oy (-) but not (+) efaroxan.
- the K + channel effect of efaroxan on the pancreatic islets is due to the (-) enantiomer.
- Fig 3 shows that the (-) enantiomer potentiates insulin secretion at a threshold glucose concentration, an effect which is not shared by the (+) enantiomer. This confirms that the dominant insulin secretion effect of efaroxan is controlled by K + channel permeability changes brought about by the (-) enantiomer.
- the ⁇ 2 -potency is expressed in terms of the potency of the compound relative to idazoxan in the rat vas deferens (in vitro) test.
- the K + channel data is in terms of percentage reversal of the reduction of 20mM glucose stimulated insulin secretion by diazoxide (250 ⁇ M) by 100 ⁇ M of test substance.
- Results in Table 2 further emphasise the unexpectedhess and unpredictability of the results with the compounds of this invention - they also stress the point that the channel effects are totally independent of any ⁇ 2 -activity that the compounds possess (ie there is in fact no relationship between ⁇ 2 -adrenoreceptors and changes in
- (+) enantiomer was shown to substantially reverse the inhibition of insulin secretion brought about by the ⁇ 2 - agonist UK 14304 whereas the (-) enantiomer was relatively ineffective (Fig 4). This is fully in agreement with other studies which have confirmed that the ⁇ 2 antagonist activity of the isopropyl analogue resides in the (+) enantiomer.
- both the (+) and (-) enantiomers of the ispropyi analogue were capaole of reversing the inhibition of insulin secretion brought about by the K + channel activator diazoxide (Fig 5).
- this activity was stereospecifically confined to the (-) enantiomer of efaroxan (Fig 2).
- the invention also includes the use of the (-) enantiomer of a compound of Formula 1 or a non-toxic salt thereof as a potassium cnannel blocking agent in the treatment of diabetes.
- the invention further inoludes a method of treating diabetes which comprises administering to humans an effective potassium channel blocking amount of the (-) enantiomer of a compound of Formula 1 or a non-toxic salt thereof.
- the invention further includes the use of the (-) enantiomer of a compound of Formula 1 or a non-toxic salt thereof in the preparation of a pharmaceutical composition as a potassium blocking agent in the treatment of diabetes without producing any significant effect of an ⁇ 2 -adreno- receptor.
- the (-) enantiomer of efaroxan may be prepared from efaroxan (in base form) by standard methods for preparing optically active enantiomers from racemic mixtures.
- efaroxan is treated in solution with a (-) optically active acid such as (-)-dibenzoyl-L-tartaric acid, the resultant (-) salt is separated and recrystallized until optical purity is obtained and the (-) enantiomer of efaroxan is obtained following addition of a base such as potassium carbonate.
- the (-) enantiomer of the compound of Formula 1 in which R is methyl may be prepared in like manner from the racemate prepared by the base catalysed alkylation of dihydrobenzofuran-2-carooxylic acid with 2-iodopropane with the resultant 2-substituted acid being converted to the 2-imidazoline using standard methods.
- compositions may be in a form suitable for oral or parenteral administration.
- Such oral compositions may be in the form of capsules, tablets, granules or liquid preparations such as elixirs, syrups or suspension.
- Tablets contain a compound of Formula 1 as hereinbefore defined or a non-toxic salt thereof in admixture with excipients which are suitable for the manufacture of tablets.
- excipients may be inert diluents such as calcium phosphate, microcrystalline cellulose, lactose, sucrose or dextrose; granulating and disintegrating agents such as starch; binding agents such as starch, gelatine, polyvinyl-pyrrolidone or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc.
- compositions in the form of capsules may contain the compound or a non-toxic salt thereof mixed with an inert solid diluent such as calcium phosphate, lactose or Kaolin in a hard gelatine capsule.
- an inert solid diluent such as calcium phosphate, lactose or Kaolin in a hard gelatine capsule.
- compositions for parenteral administration may be in the form of sterile injectable preparations such as solutions or suspensions in for example water, saline or 1,3-butane diol.
- the compositions are advantageously employed in a unit dosage form.
- the unit dosage form contains from 1 to 500mg, preferably 1 to 250mg of the compound of Formula 1 or a non-toxic salt thereof.
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Abstract
The substantially pure (-) enantiomers of 2-[2-(2-alkyl-2,3-dihydrobenzofuranyl)]-2-imidazolines of formula (1), wherein R is hydrogen or methyl, their non-toxic salts, processes for their preparation and pharmaceutical compositions thereof. Also described is a method of treating diabetes.
Description
IMIDAZOLINE DERIVATIVES
This invention relates to imidazoline derivatives, their salts, process for their preparation and pharmaceutical compositions thereof.
In our European patent specification No 00713B8 we describe and claim dihydrobenzofuranyl imidazolines of the formula
The compounds of Formula A possessed α2-adrenoreceptor antagonist activity and by virtue of such activity had potential utility for the treatment of those conditions in patients in which activity at the α2-adrenoreceptors was implicated such as endogenous depression, cardiac failure, diabetes, obesity, migraine etc.
Our subsequent investigations of the compounds of Formula A led to the identification of 2-[2-(2-ethyl-2,3- dihydrobenzofuranyl)]-2-imidazoline (in Formula A R1 =
ethyl, R2 = R3 = hydrogen; INN efaroxan). Efaroxan, as the racemate, has been shown to oe a particularly potent and selective α2-adrenoreceptor antagonist and based on those properties was identified as a potential antidiabetic drug.
We have now extended our investigations of the compounds of Formula A and have found that efaroxan and the analogous novel isopropyl compound (in Formula A R 1 = i-propyl, R2 = R3 = hydrogen) are pharmacologically different from the analogous compounds wnere R1 is hydrogen, n-propyl or longer chain alkyl. Furthermore we have now resolved efaroxan and its isopropyl analogue into their optically active enantiomers and have found that the (-) enantiomers have a most unexpected pharmacological profile.
According to this invention there is provided the (-) enantiomer of a compound of Formula 1
By (-) enantiomer of a compound of Formula 1 in substantially pure form we mean that the amount of the (+) enantiomer present does not exceed 5% and preferably does not exceed 2% .
Examples of non-toxic salts are those with inorganic
salts such as hydrochloric acid, sulphuric or phosphoric acid; or organic acids such as acetic, propionic, malonic, succinic, fumaric, tartaric or citric acid. A preferred salt is the hydrochloride.
The invention also includes pharmaceutical compositions comprising the (-) enantiomer of a compound of Formula 1 in substantially pure form or a non-toxic salt thereof, together with a pharmaceutically acceptable diluent or carrier.
The literature clearly points to the relationship between antagonism at α2-adrenαreceptors and stimulation of insulin secretion (Robertson R P and Porte D, Diaoetes, 1973, 22,1; Efendic S, Cerasi E and Luft R, Acta Endocrinologica, 1973, 74, 542-547; Linde J and Deckert T, Horm Metab Res 1973, 5, 391-395). In particular the antidiabetic effects of Ηidaglizole (DG 5128) have been attributed to α 2-antagonism (Kameda Kui-ya, Shin-etsu Ono, Isao Koyama and Yasushi Abiko, Acta Endocrinologica 1982, 99, 410-415).
Although the secretion of insulin from pancreatic islets in response to glucose stimulation is the result of a complex sequence of events, changes in potassium permeability are of major importance. Thus increased potassium permeability (potassium channel opening) reduces insulin secretion whereas the converse is true with potassium channel blockade. A number of drugs affect potassium channel permeability and the antidiabetic sulphonylureas function as potassium channel blockers. In
contrast the vasodilator diazoxide, which can induce a diabetic state, increases botassium channel permeability and therefore reduces insulin secretion.
The mechanism by which α2-antagonists stimulate insulin secretion has been related to their effects on K+ channels in pancreatic islet cells. Thus the reduction of K+ channel permeability by efaroxan was shown to occur over the same concentration range as its blockade of α2-adranoreceptors (Sehlin J , Doxey J C and Lindstrom 2 , Diabetologia, 1987, 30, 7, 580A No 503). The opposite effect was shown by UK 14304 a selective α2-agonist.
These observations were confirmed in the mouse was deferens by the work of Zimanyi I, Folly G and Vizi E S
(J. Neuroscience Res, 1988, 20, 102-103) who concluded that stimulation of α2-adrenoreceptors (by α2-agonists) leads to enhanced K+ permeability.
These results clearly indicate that there is a direct relationship between α2-adrenoreceptors and changes in K+ channel permeability in both islet and non-islet tissues.
Chan S L F and Morgan N G, (Eur J Pharmac, 1990, 176, 97-101) recently concluded that the ability of efaroxan to stimulate insulin secretion from isolated rat pancreatic islets could not be attributed to interaction of efaroxan with "classical" α2-adrenoreceptors since the effect was not reproduced by the related α2-antagonist idazoxan at the same concentration. However, very high concentrations of efaroxan were required to achieve the effect and since idazoxan is 3-5 time less potent than efaroxan an active
concentration level for idazoxan may not have oeen reached. Chan and Morgan also showed that efaroxan had a greater effect than idazoxan in reversing the inhibitory effects of diazoxide on glucose-induced insulin release, though again very high concentrations of efaroxan mere required.
It has now been shown that the α2-adrenoreceptor blocking effects of racemic α2-antagonists involving interactions with a receptor for which the natural ligand is a pure enantiomer (noradrenaline) are stereospecific with the activity residing in one enantiomer. In the case of efaroxan this is the (+) enantiomer. Table 1 snows that in various systems the selectivity of tns ( + ) over the (-) enantiomer for α2-receptors is between 300 and 5000.
1. The in vitro prejunctional α2-adrenoreceptor antagonist potencies (pA2 values) were determined in the prostate section of the rat vas deferens using previously described methodology (Doxey et al, 8r J Pharmac, 1984, 83, 713).
The α2-adrenoreceptor agonist employed in these studies was p-aminoclonidine.
2. The in vivo prejunctional α2-adrenoreceptor antagonist potencies were determined in the vas deferens of pithed rats using a previously described method (Welbourn et al, J Med Chem, 1986, 29, 2000). Antagonist potencies were determined as the dose (μ moles/Kg, iv) required to produce a 2-fold shift (DR2) of the dose-response curve to UK-14304 on the twitch response of the vas deferens.
3. The radioligand binding affinities (K1, nM) were determined from their ability to displace the saturable binding of [3H] idazoxan from α2-adrenoreceptor sites prepared from rat cerebral cortical membranes (Welbourn et al, J Med Chem, 1986, 29, 2000).
Other than in its relationship to α2-adrenoreceptor antagonism the suggestion has never been made that inhibition of K+ channel permeabiltiy is a stereospecific phenomenon. Indeed the very high concentration of efaroxan required to inhibit diazoxide's effect on pancreatic islet cells (Chan and Morgan 1990) suggests a non-specific effect.
We have now found unexpectedly that the inhibitory effect of efaroxan on K+ channel permeability (and hence its
ability to stimulate insulin secretion) resides in a single enantiomer (-), which is not the active α2-antagonist enantiomer. The data as shown in Figs 1 to 3 were determined as follows:
figure 1
Groups of isolated rat islets were incubated with 20rnM glucose, 1 μM UK 14304 and increasing concentrations of the
(+) and (-) enantiomers of efaroxan. After incubation for
50 minutes at 37°C, samples of medium were removed and assayed for insulin. Data are mean values ± SEM for 10-18 observations.
Figure 2
Groups of isolated rat islets were incubated with 20mM glucose, 250μM diazoxide and increasing concentrations of the (+) and (-) enantiomers of efaroxan. After incubation for 60 minutes at 37°C, samples of medium were removed and assayed for insulin. Data are mean values ± SEM for 10-18 observations.
Figure 3
Groups of isolated rat islets mere incubated with 8mM glucose in the presence of increasing concentrations of the (+) and (-) isomers of efaroxan. (Procedure then similar to that used in Figures 2 and 3).
In Fig 1 insulin secretion stimulated by 20mM glucose is inhibited by the α2-agonist UK14304 (1μM). This inhibitory effect is reversed in a dose-related manner by
(+) but not (-) efaroxan. This confirms that the α2- antagonist activity resides in the (+) enantiomer in
pancreatic islets as well as in non-islet cells. Fig 2 shows that insulin secretion stimulated by 20mM glucose can also be inhibited by diazoxide, a known K+ channel opening agent, and this effect is reversed oy (-) but not (+) efaroxan. Thus the K+ channel effect of efaroxan on the pancreatic islets is due to the (-) enantiomer. Fig 3 shows that the (-) enantiomer potentiates insulin secretion at a threshold glucose concentration, an effect which is not shared by the (+) enantiomer. This confirms that the dominant insulin secretion effect of efaroxan is controlled by K+ channel permeability changes brought about by the (-) enantiomer.
The α2-adrenoreceptor antagonist data and the K+ channel data for various racemic compounds of Formula A in which (R2=R3=hydrogen) are shown in Table 2. The α2-potency is expressed in terms of the potency of the compound relative to idazoxan in the rat vas deferens (in vitro) test. The K+ channel data is in terms of percentage reversal of the reduction of 20mM glucose stimulated insulin secretion by diazoxide (250μM) by 100μM of test substance.
K channel permeability within the compounds). Compounds in which R1 =H, ethyl, n-propyl and n-Dentyl (racemates) all possess appreciable α2- antagonist activity; with the exception of the latter they are equipotent being approximately twice as potent as idazoxan. Only efaroxan
(R1=ethyl) however possesses the K+ channel inhibitory properties. In contrast the comoound where R1=i-propyl has markedly reduced α2-antagonist activity yet is approximately equieffective as efaroxan in inhibiting K+ channels.
Subsequent studies with the (+) and (-) enantiomers of the isopropyl analogue of efaroxan gave further unexpected results which emphasize the unique action of the (-) isomer of efaroxan on the K+ channel. Thus in a series of experiments carried out in an identical fashion to those on the efaroxan enantiomers and as shown in Figs 4 to 6, a similar and not unexpected difference in α2-adrenoreceptor potency of the two isopropyl enantiomers was determined (Fig 4). The (+) enantiomer was shown to substantially reverse the inhibition of insulin secretion brought about by the α2- agonist UK 14304 whereas the (-) enantiomer was relatively ineffective (Fig 4). This is fully in agreement with other studies which have confirmed that the α2antagonist activity
of the isopropyl analogue resides in the (+) enantiomer.
Surprisingly however, and in contrast to the situation with the efaroxan enantiomers, both the (+) and (-) enantiomers of the ispropyi analogue were capaole of reversing the inhibition of insulin secretion brought about by the K+ channel activator diazoxide (Fig 5). As mentioned earlier with respect to efaroxan this activity was stereospecifically confined to the (-) enantiomer of efaroxan (Fig 2). Furthermore, both of the isopropyl enantiomers of the isopropyl were able to directly stimulate insulin secretion (Fig 6) an activity which was largely confined in the case of efaroxan to the (-) enantiomer (Fig 3).
It has always been recognised that the ability of efaroxan to stimulate insulin secretion through an α2-adrenoreceptor mechanism could be compromised by its actions at non-islet α2-adrenoreceptors. In particular effects on sympathetic neurones would tend to increase circulating catecholamines and this could counteract any direct effect on islet α2-adrenoreceptors. Furthermore, increased plasma catecholamines would also increase blood pressure in a group of patients which is prone to Hypertensive disease. These limitations are not apparent in the (-) enantiomer of either efaroxan or of its isopropyl analogue which influence insulin secretion directly by an action on potassium channels and which have a very low affinity for α2-adrenoreceptors.
The invention also includes the use of the (-)
enantiomer of a compound of Formula 1 or a non-toxic salt thereof as a potassium cnannel blocking agent in the treatment of diabetes. The invention further inoludes a method of treating diabetes which comprises administering to humans an effective potassium channel blocking amount of the (-) enantiomer of a compound of Formula 1 or a non-toxic salt thereof.
The invention further includes the use of the (-) enantiomer of a compound of Formula 1 or a non-toxic salt thereof in the preparation of a pharmaceutical composition as a potassium blocking agent in the treatment of diabetes without producing any significant effect of an α2-adreno- receptor.
The (-) enantiomer of efaroxan may be prepared from efaroxan (in base form) by standard methods for preparing optically active enantiomers from racemic mixtures. Thus efaroxan is treated in solution with a (-) optically active acid such as (-)-dibenzoyl-L-tartaric acid, the resultant (-) salt is separated and recrystallized until optical purity is obtained and the (-) enantiomer of efaroxan is obtained following addition of a base such as potassium carbonate. The (-) enantiomer of the compound of Formula 1 in which R is methyl may be prepared in like manner from the racemate prepared by the base catalysed alkylation of dihydrobenzofuran-2-carooxylic acid with 2-iodopropane with the resultant 2-substituted acid being converted to the 2-imidazoline using standard methods.
The examples illustrate the preparation of the (-) and
(+) enantiomers of efaroxan and of the (-) and ( + ) enantiomers of its isoprooyl analogue. The optical rotations were measured on a Perkin Elmer 141 dolarimeter. EXAMPLE 1
Efaroxan (-) Enantiomer
The free base of efaroxan (6.0g) was dissolved in hot acetone (180ml) and added to a solution of (-)-dibenzoyl-L- tartaric acid (10.44g) in hot acetone (180ml). The cloudy solution was allowed to cool to room temperature and the resulting white solid was filtered off, washed with diethyl ether and dried to give (-) efaroxan dibenzoyltartrate salt yield 14.1g, optical rotation [α]D=-82.07° (c=1.10 methanol).
The salt (13.8g) was recrystallized from methanol/ diethyl ether to give a white solid: yield 4.2g, optical rotation [α]D=-125.2° (c=1.03, methanol); 4.0g of the salt was recrystallized a second time from methanol/diethyl ether to give a sample whose rotation failed to increase on further crystillization: yield 3.2g; optical rotation [α]D=-128.1°(c=1.03, methanol).
0.3g of the purified salt was stirred at room temperature with a solution of K2CO3(3g in 10ml H2O) and the resulting solution was extracted with dichloromethane. The organic layer was dried and evaporated to give the (-) enantiomer of efaroxan as a white solid; yield 0.09g, optical rotation [α]D=-53.8°(c=1.01, methanol), m.pt. HCl salt 258-261°C.
EXAMPLE 2
Efaroxan (+ ) Enantiomer
The free base of efaroxan (5.0g) was dissolved in hot acetone (180ml) and added to a solution of (+)-dibenzoyl-D- tartaric acid (8.7g) in not acetone (180ml). The cloudy solution was allowed to cool to room temperature and the resulting white solid was filtered off, washed with diethyl ether and dried to give (+) efaroxan dibenzoyltartrate salt yield 8.4g, optical rotation [α]D=+90.04°(c=1.01 methanol).
The salt (8.2g) was recrystallized from methanol/ diethyl ether to give an off-white solid: yield 4.3g, optical rotation [α]D=+116.9°(c=1.05, methanol); 4.0g of the salt was recrystallized a second time from methanol/ diethyl ether to give a sample whose rotation failed to increase on further crystillization: yield 1.1g; optical rotation [α]D=+118.7°(c=1.03, methanol).
0.3g of the purified salt were stirred at room temperature with a solution of K2CO3(3g in 10ml H2O) and the resulting solution was extracted with dichloromethane. The organic layer was dried and evaporated to give the (+) enantiomer of efaroxan as a white solid; yield 0.09g, optical rotation [α]D=+52.8°(c=1.00, methanol).
EXAMPLE 3
(-)-2-[2-(2-Isopropyl-2,3-dihydrobenzofuranyl)3-2- imidazoline
The free base of 2-[2-(2-isopropyl-2,3-dihydrobenzofuranyl)]-2-imidazoline (4g) was dissolved in hot acetone
(110ml) and added with stirring to a solution of (-)- dibenzoyl-L-tartaric acid (6.54g) in hot acetone (85ml).
The stirred solution was allowed to cool, stirred for 2
hours at room temperature, and the resulting white solid was removed by filtration and dried to give (-)-2-[2-(2-iso- propyl-2, 3-dihydrobenzofuranyl)]-2-imidazoline dibenzoyl- tartrate salt: yield 4.97g; optical rotation [α]D = -106.6° (c = 1.00, methanol).
The salt (4.8g) was recrystallised from methanol/ diethyl ether to give a white solid: yield 3.4g; optical rotation [α]D = -116.1° (c = 1, methanol). 3.25g of the salt was recrystallised a second time from methanol/diethyl ether to give a sample whose rotation failed to increase on further crystallisation: yield 2.32g; optical rotation [α]D = -122.2° (c = 1, methanol).
1.95g of the purified salt was partitioned between dichloromethane and 10% aqueous sodium carbonate solution, and the organic layer was washed with further 10% sodium carbonate solution. The organic layer was washed with water, dried and evaporated to give (-)-2-[2-(2-isopropyl-2, 3-dihydrobenzofuranyl)]-2-imidazoline as a white solid: yield 0.75g; optical rotation [α]Q = -29.4° (c = 1, methanol), m p HCl salt 277° (dec).
EXAMPLE 4
(+)-2-[2-(2-Isopropyl-2,3-dihydrobenzofuranyl)1-2- imidazoline
The mother liquors from the crystallisations of Example 3 (1 x acetone, 2 x methanol/diethyl ether) were combined and the solvents removed in vacuo). The residue was partitioned between dichloromethane and 5% aqueous sodium carbonate solution, and the aqueous layer extracted with
further dichloromethane. The organic phases were combined and washed successively with further sodium carbonate solution, water and saturated sodium chloride solution. The solution was dried and evaporated to afford a residue enriched in (+)-2-[2-(2-isopropyl-2,3-dihydrobenzofuranyl)]- 2-imidazoline (2.95g).
A portion of this material (2.85g) was dissolved in hot acetone (60ml) and added to a stirred solution of (+)- dibenzoyl-D-tartaric acid (4.65g) in hot acetone (60ml). The stirred solution was allowed to cool, stirred for 3 hours at room temperature, and the resulting white solid was removed by filtration and dried to give (+)-2-[2-(2- isopropyl-2,3-dihydrobenzofuranyl)]-2-imidazoline dibenzoyltartrate salt: yield 4.82g; optical rotation [ α ] D = +112.8° (c = 1, methanol).
The salt (4.6g) was recrystallised from methanol/ diethyl ether to give a white solid: yield 3.32g; optical rotation [α]D = +120.8° (c = 1, methanol). 3.1g of the salt was recrystallised a second time from methanol/diethyl ether to give a sample whose rotation failed to increase on further crystallisation: yield 2.75g; optical rotation [α]D = +121.4° (c = 1, methanol).
1.5g of the purified salt was partitioned between dichloromethane and 1 0% aqueous sodium carbonate solution, and the organic layer was washed with further sodium carbonate solution. The organic layer was washed with water, dried and evaporated to give (+)-2-[2-(2-isopropyl-2, 3-dihydrobenzofuranyl)]-2-imidazoline as a white solid:
yield 0.57g; optical rotation [α]D = +29.7° (c = 1, methanol), m p HCl salt 274° (dec).
The pharmaceutical compositions may be in a form suitable for oral or parenteral administration. Such oral compositions may be in the form of capsules, tablets, granules or liquid preparations such as elixirs, syrups or suspension.
Tablets contain a compound of Formula 1 as hereinbefore defined or a non-toxic salt thereof in admixture with excipients which are suitable for the manufacture of tablets. These excipients may be inert diluents such as calcium phosphate, microcrystalline cellulose, lactose, sucrose or dextrose; granulating and disintegrating agents such as starch; binding agents such as starch, gelatine, polyvinyl-pyrrolidone or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc.
Compositions in the form of capsules may contain the compound or a non-toxic salt thereof mixed with an inert solid diluent such as calcium phosphate, lactose or Kaolin in a hard gelatine capsule.
Compositions for parenteral administration may be in the form of sterile injectable preparations such as solutions or suspensions in for example water, saline or 1,3-butane diol.
For the purpose of convenience and accuracy of dosing the compositions are advantageously employed in a unit dosage form. For oral administration the unit dosage form contains from 1 to 500mg, preferably 1 to 250mg of the
compound of Formula 1 or a non-toxic salt thereof.
Claims
1. The (-) enantiomer of a compound of Formula 1
2. (-)-2-[2-(2-Ethyl-2,3-dihydrobenzofuranyl)]-2- imidazoline in substantially pure form and its non-toxic salts.
3. A pharmaceutical composition comprising a compound as claimed in Claim 1 or Claim 2 or a non-toxic salt thereof, together with a pharmaceutically acceptable diluent or carrier.
4. A pharmaceutical composition as claimed in Claim 3 for oral administration in unit dosage form wherein each unit contains from 1 to 500mg of the compound or a non-toxic salt thereof.
5. The use of a compound as claimed in Claim 1 or Claim 2 or a non-toxic salt thereof as a potassium channel blocking agent in the treatment of diabetes.
6. The use of a compound as claimed in Claim 1 or Claim 2 or a non-toxic salt thereof in the preparation of a pharmaceutical composition as a potassium channel blocking agent in the treatment of diabetes without producing any significant effect at an α2-adrenoreceptor.
7. A method of treating diabetes which comprises administering to humans an effective potassium channel blocking amount of a compound as claimed in Claim 1 αr Claim
2 or a non-toxic salt thereof.
8. A process for the preparation of the (-) enantiomer of a compound of Formula 1 of Claim 1 wherein R is hydrogen or methyl in which process a compound of Formula 1 in the form of the racemate is treated in solution with a (-) optically active acid, the resultant (-) salt is separated and recrystallised until optical purity is obtained and thereafter the (-) enantiomer of the compound of Formula 1 is obtained following addition of a base.
9. A process as claimed in Claim 8 wherein the (-) optically active acid is (-)-dibenzoyl-L-tartaric acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909020128A GB9020128D0 (en) | 1990-09-14 | 1990-09-14 | Imidazoline derivatives |
| GB9020128.6 | 1990-09-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992005171A1 true WO1992005171A1 (en) | 1992-04-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1991/001542 WO1992005171A1 (en) | 1990-09-14 | 1991-09-10 | Imidazoline derivatives |
Country Status (6)
| Country | Link |
|---|---|
| AU (1) | AU8531891A (en) |
| GB (1) | GB9020128D0 (en) |
| IE (1) | IE912979A1 (en) |
| IL (1) | IL99469A0 (en) |
| PT (1) | PT98970A (en) |
| WO (1) | WO1992005171A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5399587A (en) * | 1993-12-13 | 1995-03-21 | Merck & Co., Inc. | Biologically active compounds |
| US5498623A (en) * | 1991-12-12 | 1996-03-12 | Orion-Yhtyma Oy | 4(5) substituted imidazoles and their preparation and use |
| WO1996035682A1 (en) * | 1995-05-10 | 1996-11-14 | Pierre Fabre Medicament | Method for preparing an optically pure benzofuran carboxylic acid and use thereof for preparing efaroxan |
| WO2000015624A1 (en) * | 1998-09-10 | 2000-03-23 | Pierre Fabre Sante, Societe Anonyme | 2-ethyl-2,3-dihydrobenzofuran-carboxylic acid ester derivative, preparation method and use for preparing efaroxan derivatives |
| WO2000076990A1 (en) * | 1999-06-16 | 2000-12-21 | Astrazeneca Ab | New compounds |
| US6410562B1 (en) | 1998-12-18 | 2002-06-25 | Eli Lilly And Company | Hypoglycemic imidazoline compounds |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0071368A1 (en) * | 1981-07-28 | 1983-02-09 | Reckitt And Colman Products Limited | Imidazoline derivatives |
-
1990
- 1990-09-14 GB GB909020128A patent/GB9020128D0/en active Pending
-
1991
- 1991-08-22 IE IE297991A patent/IE912979A1/en unknown
- 1991-09-10 WO PCT/GB1991/001542 patent/WO1992005171A1/en not_active Application Discontinuation
- 1991-09-10 AU AU85318/91A patent/AU8531891A/en not_active Withdrawn
- 1991-09-12 IL IL99469A patent/IL99469A0/en unknown
- 1991-09-13 PT PT98970A patent/PT98970A/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0071368A1 (en) * | 1981-07-28 | 1983-02-09 | Reckitt And Colman Products Limited | Imidazoline derivatives |
Non-Patent Citations (2)
| Title |
|---|
| Arch. int. Pharmacodyn., vol.269, no. 2, February 1984, G. Joly et al: "Pre- and Post- synaptic alfa-Adrenoceptor Blocking Properties of a New Dihydrobenzofurane Derivative (Imidazolinyl-2)-2-dihydro 2,3 benzofurane (S 9871) and its Stereoisomers in Rats", pages 277-286, see the whole article * |
| J. Med. Chem., vol. 20, no. 5, May 1984, C.B. Chapleo et al: "alfa-Adrenoreceptor reagents. 2. Effects of Modification of the 1,4-Benzodioxan Ring System on alfa-Adrenoreceptor Activity", pages 570-576 see compound 13 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5498623A (en) * | 1991-12-12 | 1996-03-12 | Orion-Yhtyma Oy | 4(5) substituted imidazoles and their preparation and use |
| US5399587A (en) * | 1993-12-13 | 1995-03-21 | Merck & Co., Inc. | Biologically active compounds |
| WO1996035682A1 (en) * | 1995-05-10 | 1996-11-14 | Pierre Fabre Medicament | Method for preparing an optically pure benzofuran carboxylic acid and use thereof for preparing efaroxan |
| FR2733983A1 (en) * | 1995-05-10 | 1996-11-15 | Pf Medicament | PROCESS FOR PREPARING AN OPTICALLY PURE BENZOFURAN CARBOXYLIC ACID DERIVATIVE AND USE THEREOF FOR PREPARING EFAROXAN |
| US5880296A (en) * | 1995-05-10 | 1999-03-09 | Pierre Fabre Medicament | Method for preparing an optically pure benzofuran carboxylic acid and use thereof for preparing efaroxan |
| AU708894B2 (en) * | 1995-05-10 | 1999-08-12 | Pierre Fabre Medicament | Process for the preparation of an optically pure benzofurancarboxylic acid derivative and its use for preparing efaroxan |
| WO2000015624A1 (en) * | 1998-09-10 | 2000-03-23 | Pierre Fabre Sante, Societe Anonyme | 2-ethyl-2,3-dihydrobenzofuran-carboxylic acid ester derivative, preparation method and use for preparing efaroxan derivatives |
| FR2784989A1 (en) * | 1998-09-10 | 2000-04-28 | Fabre Pierre Sante | 2-ETHYL-2,3-DIHYDROBENZOFURAN-CARBOXYLIC ACID ESTER DERIVATIVE, PREPARATION METHOD AND USE FOR THE PREPARATION OF EFAROXAN DERIVATIVES |
| US6410562B1 (en) | 1998-12-18 | 2002-06-25 | Eli Lilly And Company | Hypoglycemic imidazoline compounds |
| WO2000076990A1 (en) * | 1999-06-16 | 2000-12-21 | Astrazeneca Ab | New compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9020128D0 (en) | 1990-10-24 |
| AU8531891A (en) | 1992-04-15 |
| IE912979A1 (en) | 1992-02-25 |
| PT98970A (en) | 1992-07-31 |
| IL99469A0 (en) | 1992-08-18 |
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